The interaction between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease

Parkinson’s disease (PD) is clinically, pathologically, and etiologically diverse and complex combinations of genetic susceptibility and environmental risk factors like age, gender, estrogen status, race/ethnicity, exposure to pesticides, and head trauma play roles in the pathogenesis. Genetic research has identified eleven PARK loci in familial cases and genotyping technology has allowed genome-wide approaches in large populations of patients with sporadic PD. Neuropathologic studies have defined and characterized more than 30 proteins with the core filament of α-synuclein in the Lewy body inclusions of idiopathic PD. Analysis of Lewy body pathology has outlined progressive disease stages in which the intracellular deposition of α-synuclein affects medullary sites before more rostral brain regions and the late stages of involvement of cortical association neurons. In PD, there is evidence of protein misfolding, aggregation, and abnormal neuronal apoptosis. Toxin-based and recent gene mutation-based animal models of PD in mammals, flies, fish, and worms have reproduced the progressive motor and non-motor deficits observed in PD patients and shown dopamine dysfunction and delayed loss of dopaminergic neurons in the substantia nigra. Oxidative stress plays a key role in the pathogenesis of PD and the demonstration of nitrated protein within Lewy bodies and neurites provides evidence of oxidative damage in the pathogenesis of PD. Reduction in the mitochondrial enzyme complex I in PD renders neurons vulnerable to unstable oxygen free radicals and causes alpha-synuclein to aggregate into fibrils and lead to dopaminergic neuronal loss. The DJ-1 gene has antioxidant function in the cellular response to oxidative stimuli and DJ-1 is oxidatively damaged in the brains of PD patients. The occurrence of a parkinsonian syndrome in families with mutations in the DJ-1 gene also supports a role for oxidative stress in the pathogenesis of PD. Therapeutic approaches that could prevent or limit oxidative reactions in PD represent a viable strategy for the development of newer antiparkinsonian drugs.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuron-specific degeneration in the substantia nigra. A number of gene mutations and deletions have been reported to play a role in the pathogenesis of familial PD. Moreover, a number of pathological and pharmacological studies on sporadic PD and dopaminergic neurotoxin-induced parkinsonism have hypothesized that mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system all play important roles in the pathogenesis and progress of PD. However, these hypotheses do not yet fully explain the mechanisms of dopaminergic neuron-specific cell loss in PD. Recently, the neurotoxicity of dopamine quinone formation by auto-oxidation of dopamine has been shown to cause specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and dopaminergic neurotoxin-induced parkinsonism. Furthermore, this quinone formation is closely linked to other representative hypotheses in the pathogenesis of PD. In this article, we mainly review recent studies on the neurotoxicity of quinone formation as a dopaminergic neuron-specific oxidative stress and its role in the etiology of PD, in addition to several neuroprotective approaches against dopamine quinone-induced toxicity.

Chapter 17 - Prion-like propagation of pathology in Parkinson disease

Parkinson's disease (PD) is characterized by the accumulation of fibrillar alpha-synuclein (alpha-Syn) inclusions known as Lewy bodies (LBs) and Lewy neurites. Mutations in the alpha-Syn gene or extra copies thereof cause familial PD or dementia with LBs (DLB) in rare kindreds, but abnormal accumulations of wildtype alpha-Syn also are implicated in the pathogenesis of sporadic PD, the most common movement disorder. Insights into mechanisms underlying alpha-Syn mediated neurodegeneration link alpha-Syn oligomerization and fibrillization to the onset and progression of PD. Thus, inhibiting alpha-Syn oligomer or fibril formation is a compelling target for discovering disease modifying therapies for PD, DLB, and related synucleinopathies. Although amyloid dyes recognize alpha-Syn fibrils, efficient detection of soluble oligomers remains a challenge. Here, we report a novel fluorescence polarization (FP) technique for examining alpha-Syn assembly by monitoring changes in its relative molecular mass during progression of normal alpha-Syn from highly soluble monomers to higher order multimers and thence insoluble amyloid fibrils. We report that FP is more sensitive than conventional amyloid dye methods for the quantification of mature fibrils, and that FP is capable of detecting oligomeric alpha-Syn, allowing for rapid automated screening of potential inhibitors of alpha-Syn oligomerization and fibrillization. Furthermore, FP can be combined with an amyloid dye in a single assay that simultaneously provides two independent biophysical readouts for monitoring alpha-Syn fibrillization. Thus, this FP method holds potential to accelerate discovery of disease modifying therapies for LB PD, DLB, and related neurodegenerative synucleinopathies.

Parkinson’s disease (PD) is the second most common neurodegenerative disease among the elderly. While sporadic PD constitutes 99% of the cases, the remaining 1% is of genetic origin. The neuropathological hallmarks of PD are progressive degeneration of dopaminergic (DA) neurons and presence of Lewy neurites and Lewy bodies (LBs) intracytoplasmic proteinaceous inclusions that contain -synuclein (SYN), synphilin-1, components of the ubiquitin proteasomal pathway and parkin (Dawson, 2006). The loss of DA neurons in substantia nigra pars compacta (SNpc) results in decreased signalling in the striatum thereby giving rise to motor defects like resting tremor, bradykinesia, rigidity and posture instability. Besides DA neuronal loss, microglial activation and increased astroglial and lymphocyte infiltration also occur in PD. A role for inflammation in PD has been inferred from the identification of human leukocyte antigen (HLA)-DR positive reactive microglia in the brains of PD patients (McGeer et al., 1988). Additionally, levels of proinflammatory cytokines like IL-6, IL-1, TNF have been found to be elevated in the blood and cerebrospinal fluid (CSF) of PD patients (Nagatsu & Sawada, 2005; Dawson, 2006) Although these inflammatory components might serve as useful biomarkers, the aetiology of striatal DA degeneration still remains enigmatic. In the last decade, identification of mutations in several distinct genes (LRRK2, parkin, PINK1, DJ-1, -synuclein, MAPT, UCHL1 etc) linked to different forms of familial Parkinsonism has imparted a new direction to understanding PD pathogenesis (Tong & Shen, 2009). The question as to how seemingly divergent genes cause PD still remains unanswered, as there is no common molecular pathway involving these gene products. While parkin, -synuclein (SYN) and ubiquitin C-terminal hydrolase L1 (UCHL1) are functionally associated with the cellular ubiquitin proteasomal system (UPS), DJ-1 and PINK1 protect against oxidative stress and mitochondrial dysfunction. More recently, microarray analysis of SNpc from parkinsonian brain (Mandel et al., 2005) has shown that 68 genes related to protein degradation, signal transduction, dopaminergic transmission, iron transport and glycolysis are downregulated. Prominent among these are the protein chaperone HSC-70, subunits of the UPS and SKP1A, a member of the E3 ubiquitin ligase complex. Therefore, it is most likely that impairment in energy metabolism and/or alterations in UPS are the underlying mechanisms for PD pathogenesis (Eriksen et al., 2005; Mandel et al., 2005). Current PD treatment regimes can be divided into three categories: symptomatic, protective and restorative. Only symptomatic treatment via the administration of L-dopa and other

Inflammation-associated peripheral blood cells and serum lipid levels are associated with Parkinson's disease.

Emerging concepts of mitochondrial dysfunction in Parkinson’s disease progression: Pathogenic and therapeutic implications

Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological αSyn was mitochondrial bound. In vitro, αSyn PFF displayed a stronger binding to purified mitochondria than did αSyn monomer, revealing a preferential mitochondria binding by aggregated αSyn. This selective mitochondrial ps-αSyn accumulation was confirmed in other neuronal and animal αSyn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with αSyn aggregation (α-synucleinopathies). We also showed that the mitochondrial ps-αSyn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological αSyn, pathogenic αSyn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for α-synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-αSyn and the mitochondria is a therapeutic target for α-synucleinopathies.

Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease.

Parkinson’s Disease (PD) is generally considered a movement disorder characterized by loss of dopaminergic neurons in the central nervous system (CNS), most notably in the substantia nigra. The pathogenesis of the neuronal degeneration is not completely understood but is characterized by abnormal protein deposits forming characteristic neuronal inclusions, which are visible by light microscopy of autopsy samples, and termed Lewy bodies. α-Synuclein is one of the proteins found in these inclusions and has attracted interest because mutations of the gene encoding for this protein are found in familiar cases of PD. Most of the disability associated with PD is indeed the result of this CNS defect, and the treatment is aimed at increasing dopamine levels in the CNS, while avoiding as much as possible an increase in the periphery. Less widely recognized is the fact that orthostatic hypotension can occur in PD patients and can become symptomatic and disabling in a significant proportion of patients. The incidence of documented orthostatic hypotension in PD, in community-based studies, ranges from 10% to 40%. Orthostatic hypotension in PD is commonly attributed to the known adverse effects of dopaminergic drugs. However, over the last decade there is growing evidence that peripheral nerves, particularly autonomic neurons, are also involved in PD. Lewy body inclusions, containing α-synuclein, have been found in peripheral autonomic neurons in autopsy cases of otherwise classic PD.1 Microscopically, eosinophilic ubiquitin- and α-synuclein–positive Lewy Bodies and Lewy neurites are not only found in the substantia nigra and locus ceruleus but also are widespread in ganglions cells …

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as alpha-synuclein and parkin, suggest a role for the ubiquitin-proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause alpha-synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.

Parkinson's disease (PD) is one of the severe neurodegenerative disorders characterized by a deficiency of dopamine in the substantia nigra. The implicated factors for this include mitochondrial dysfunction, gut dysbiosis, and alteration in the signaling pathways. Overall, these events lead to the generation and aggregation of misfolding proteins, i.e., Lewy bodies. These aggregates contribute to the production of oxidative stress, inflammation, and neurotransmission imbalance. Hence, impaired cognition and body movements in the PD patients. There are several conventional treatments, such as synthetic drugs and herbal drugs, used to mitigate PD. Despite having enormous potential, their use is limited due to their low permeability, low solubility, and complexation in standardization. However, with the advancement in technology, different NDDS (Novel drug delivery systems) such as vesicular drug delivery systems, SNEDDS (Self-Nanoemulsifying Drug Delivery System), NPs (Nanoparticles), NLCs (Nano-structure lipid carrier), SLN (Solid lipid nanoparticles), quantum dots, and dendrimers have been explored to overcome the limitations of conventional treatments. Hence, the present review emphasizes a brief introduction to PD, pathogenesis of PD, signaling pathways, biomarkers, conventional treatments, need for NDDS, and Applications of NDDS in PD. Additionally, patents, clinical trials, and ongoing clinical trials are also covered in the present manuscript.

Le corps de Lewy, marqueur abusif de la maladie de Parkinson ?

Lewy bodies and Lewy neurites in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies. They comprise amyloid-like fibrils composed of α-synuclein (αS), a small protein (~14kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of these diseases, the research for disease-modifying drugs has focused on modification of the αS aggregation process in the brain. Recent studies using synthetic αS peptides, a cell culture model, transgenic mice models, and human samples such as cerebrospinal fluids and the blood of PD patients have suggested that pre-fibrillar forms of αS (i.e., oligomers) are more critical than fibrillar forms (such as Lewy bodies) in the pathogenesis of α-synucleinopathies. Based on the accumulating evidence that oligomers play a central role in the pathogenesis of PD and other α-synucleinopathies (the "oligomer hypothesis"). This report reviews the recent findings regarding the oligomer hypothesis in the research of α-synucleinopathies.

Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.